This invention relates to methods of administering pharmaceutical materials, in particular N-substituted benzamides, phenothiazines, and acid addition salts thereof, to human patients, as well as to formulations containing such materials. In an important specific sense, to which detailed reference will be made herein for purposes of illustration, the invention is directed to methods and formulations for administering acid addition salts of metoclopramide to human patients.
Metoclopramide is currently available in acid addition salt form, as metoclopramide hydrochloride, for administration to human patients as an antiemetic (e.g., in conjunction with chemotherapy) and for other purposes. It has also been discovered that metoclopramide and other N-substituted benzamides and their acid addition salts can enhance the cytotoxicity of chemotherapeutic agents and radiation. Commercially available formulations of metoclopramide hydrochloride are in physiologic saline solution, to which sodium metabisulfite has sometimes been added as a preservative. Typically or conventionally, these formulations are prepared for intravenous (i.v.) injection or oral administration.
The commercial formulations of metoclopramide hydrochloride have pH ranges within outer limits of about 2 to 6.5, depending inter alia on concentration. At least within these limits, it has been considered that the pH of the formulation does not affect the biological activity of the drug. A reason for the acidity of the formulations is that the acid addition salts of metoclopramide are freely soluble in aqueous vehicles whereas the free-base form is quite insoluble in water.
Although some commercial metoclopramide formulations are sold with an indicated pH range extending up to 6.5, in fact the pH of such formulations tends to be variable and/or unstable within that range and is commonly substantially below 6.5 at least by the time the formulation is administered to a patient, owing, for instance, to auto-oxidation effects. Moreover, the formulations with a nominal pH ranging up to 6.5 are highly dilute, e.g. having a metoclopramide hydrochloride concentration of 5 mg/ml. Present-day commercial formulations with significantly higher concentrations, exemplified by 100 mg/ml, have pH values of 4.5 or less.
Heretofore it has been found that metoclopramide acid addition salts in known formulations can have extrapyramidal side effects when administered to humans. These effects are undesirable and, in some instances, may restrict or prevent use of the drug.
In specific aspects, the present invention relates to the bioavailability of intramuscular (i.m.) injections of metoclopramide and its acid addition salt forms. More particularly, this invention relates pH adjustment of acid addition salt solutions of N-substituted benzamides and phenothiazines such as metoclopramide to altered biological responses important to the development of undesirable side effects of these types of drug for clinical use to prevent emesis or to enhance radio- and chemotherapies such as the local tissue toxicity at the site of i.m. injection or reduction in the extra-pyramidal side effect of sedation.
Metoclopramide and other pharmacologically active N-substituted benzamides and phenothiazines are offered in commercial form as acid addition salts (1993 Physician's Desk Reference), presumably because this form is freely soluble in aqueous solution whereas the free base form is quite water insoluble. Hence, the acid addition salts of metoclopramide and other N-substituted drugs are pharmaceutically superior forms for bioavailability via a variety of routes of administration.
U.S. Pat. No. 4,888,354 teaches that "By employing a free base-acid addition salt mixture of active ingredients, it has been found that penetration enhancement of the active ingredient is greatly improved as compared to use of either the free base or acid addition salt alone at the same concentration levels. In most cases, the rate of penetration is greater than the sum of the base and acid addition salt when applied separately." The endpoint used was skin penetration of metoclopramide. This prior art is clearly distinguished from the present invention in that it pertains only to penetration of drug through skin membranes and not to any biological response modification associated to either the base or acid addition salt forms of metoclopramide or any combinations thereof.
U.S. Pat. No. 4,536,386 discloses that "High doses of metoclopramide or a pharmaceutical salt thereof is administered intravenously to human cancer patients undergoing cisplatin chemotherapy to prevent emesis." This patent teaches that either metoclopramide (by implication the base) or an acid addition salt can inhibit the biological response of emesis, but it does not teach that any combination of these two forms would either enhance or inhibit emesis. Furthermore, it was emphasized that the commercial metoclopramide acid addition salt formulation containing physiologic saline (Reglan, a product of Robbins) was the preferred form of the drug for intravenous injection. There was no recognition of the concept that the sodium chloride present in the formulation of metoclopramide might influence the antiemetic effects compared to either the pure acid addition salt or free base forms, or that pH adjustment of acid addition salt formulations of metoclopramide might produce superior antiemetic effects or mediate reduced extrapyramidal side effects.
European patent application No. 88201795.7 and several other recent scientific reports (Kjelle'n et al., Br. J. Cancer 59: 247-250, 1989; Lybak et al., Int. J. Rad. Oncol. Biol. Phys. 19: 1419-1424, 1990; Lybak et al., Anti-Cancer Drugs 2: 375-382, 1991; Lybak et al., Acta Oncologica 31: 469-474, 1992; Salford et al., Anti-Cancer Drugs 3: 267-272, 1992) have also revealed that a commercial preparation of a metoclopramide acid addition salt (Lundbeck AB, Copenhagen) can enhance the cytotoxic action of radiation and several chemotherapy drugs. However, again these reports did not disclose whether the base or acid addition salt forms of metoclopramide or the presence of other formulation ingredients such as sodium chloride or sodium metabisulfite could modify in any way the biological response of radio- or chemotherapeutic sensitization or influence the extrapyramidal side effects of the drug.